tbuckley/cabot-search huggingface dataset:
Abstract 2602: Combined inhibition of AXL and ATR enhances cell death and immune response in small cell lung cancer
Authors: Kavya Ramkumar, Azusa Tanimoto, C. Allison Stewart, Qi Wang, Li Shen, Robert J. Cardnell, B. Leticia Rodriguez, Don L. Gibbons, Jing Wang, Carl M. Gay, Lauren A. Byers
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) is an aggressive lung tumor of neuroendocrine origin with a dismal 5-year survival rate. Despite high response rates to initial therapy, rapid development of therapeutic resistance limits overall survival. There are also limited treatment options, particularly in the relapsed setting. Our group and others have shown that AXL, a TAM family receptor tyrosine kinase that is highly expressed in mesenchymal tumors, mediates resistance to chemotherapy, radiation and targeted therapies in SCLC, non-small cell lung cancer and other cancers, through its roles in driving epithelial to mesenchymal transition and DNA damage repair. AXL has also been implicated in immune escape. Based on these findings, we hypothesize that AXL targeting may be a potential therapeutic approach in SCLC. We screened BGB324 (bemcentinib), a selective small-molecule AXL inhibitor in clinical trials for various advanced solid tumors, in a panel of 60 human SCLC cell lines using cell viability assays. The SCLC cell lines showed a range of sensitivities, with IC50 values ranging from 41 nM to 10 µM (median IC50 3.1 µM) with NeuroD1-driven SCLC cell lines being highly sensitive to BGB324 (ANOVA p&amp;lt;0.05). BGB324 also showed potent inhibition of tumor growth in an in vivo SCLC model. BGB324 further combined synergistically with an ATR inhibitor (AZD3738) and induces significant DNA damage. In a syngeneic model of SCLC, the combination of BGB324, AZD6738 and an anti-PDL1 antibody combination also induced significant tumor regression. Together, these promising findings show that AXL inhibition may be effective in SCLC and support further investigation of AXL and ATR inhibitor combinations with immune checkpoint blockade. Citation Format: Kavya Ramkumar, Azusa Tanimoto, C. Allison Stewart, Qi Wang, Li Shen, Robert J. Cardnell, B. Leticia Rodriguez, Don L. Gibbons, Jing Wang, Carl M. Gay, Lauren A. Byers. Combined inhibition of AXL and ATR enhances cell death and immune response in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2602.
Abstract 3558: A novel and versatile cytokine empowered DNA vaccine platform with superior immune activating potential
Authors: Audun Beraas, Pierre Dillard, Judith Jing Wong, Christian Winther Wold, Eirik Solbakken, Linn Guro Oslen, Joel Benjamin Heim, Stalin Chellappa, Agnete Fredriksen, Mikkel Wandahl Pedersen, Stine Granum
Journal: Cancer Research (2022)

Abstract Immunotherapy, in particular Immune Checkpoint Blockade (ICB) has been regarded as the next standard of care for many solid tumor indications. Yet, a significant proportion of patients do not respond to therapy. More specifically, failure of ICB has been linked to the absence of an anti-tumor immune response that can be boosted or revitalized. Cancer vaccines that are designed to elicit such response by educating the host immune system to recognize tumor antigens, are therefore considered a key next generation therapeutic modality for the treatment of human cancers. Various vaccine platforms have been developed over the years, but recent advances in delivery technologies combined with the intrinsic qualities of the DNA matrix have positioned DNA vaccines as a safe and flexible alternative to other types of vaccine technologies. Vaccibody is developing DNA vaccines that allows specific targeting of tumors antigens to Antigen Presenting Cells (APCs), thus maximizing the elicited immune response. Here we present a second-generation version of our DNA platform in which our vaccibody molecule can be co-expressed with immune-stimulatory proteins from one plasmid using a multicistronic design. Compared to the vaccibody molecule alone the simultaneous expression of selected immune stimulatory cytokines was shown to boost the overall immune response almost 3-fold to drive a potent anti-tumor response. These data demonstrate the flexibility and potential of DNA vaccines as well as the advantages of combining an APC targeted delivery of tumor specific antigens together with a local production of immune stimulatory proteins. Citation Format: Audun Beraas, Pierre Dillard, Judith Jing Wong, Christian Winther Wold, Eirik Solbakken, Linn Guro Oslen, Joel Benjamin Heim, Stalin Chellappa, Agnete Fredriksen, Mikkel Wandahl Pedersen, Stine Granum. A novel and versatile cytokine empowered DNA vaccine platform with superior immune activating potential [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3558.
Abstract 1891: Identifying new therapeutic antibodies using the RenMice™ HiTS Platform
Authors: Xiaoqian Zhang, Shujin Zhang, Tianquan Jin, Xin Ji, Jing Zhang
Journal: Cancer Research (2022)

Abstract Over the past decade, an increasing number of therapeutic antibodies have been approved to target cancer. However, the process of identifying new therapeutic antibodies is routinely hampered by limitations in the traditional discovery process, including immune tolerance of highly homologous genes, and challenges with antibody sequence humanization, clone selection and drug efficacy and safety evaluation. RenMice™ HiTS (Hyperimmune Target Specific) is a collection of chromosome engineered mice with fully human immunoglobulin variable domains replacing mouse counterparts, each with a specific drug target gene knocked out. The goal of the RenMice™ HiTS platform is to overcome the challenges of traditional antibody drug discovery and increase the diversity of antibody paratopes and sequences which recognize functional epitopes. Immunization of target-specific RenMice™ generates a greater diversity of antibodies, including those that recognize the conserved regions between the antigen and the endogenous proteins of the immunized host. The platform is ideal for challenging targets, such as proteins with high homology between human and mouse, or multi-pass transmembrane proteins (eg. GPCRs/ion channels). The platform can be used to generate antibodies that cross-react with human, monkey, dog, and mouse targets, using a hybrid immunization strategy with both human and mouse/dog antigen. Generation of these species cross-reactive antibodies allows for high-throughput in vivo efficacy screening using wild-type mice. It is also possible to predict the preliminary response and toxicity in dogs with these cross-reactive antibodies. Thus, selection of the best antibody candidate based on in vivo efficacy and safety allows for a streamlined and successful preclinical phase. In conclusion, the RenMice™ HiTS platform facilitates the generation of antibodies with better developability properties that recognize challenging targets and novel epitopes. Citation Format: Xiaoqian Zhang, Shujin Zhang, Tianquan Jin, Xin Ji, Jing Zhang. Identifying new therapeutic antibodies using the RenMice™ HiTS Platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1891.
Abstract 2958: Chromatin repressor complex as a converge point of RAS and PP2A activities in lung cancer
Authors: Mukund Sharma, Anna Aakula, Francesco Tabaro, Karolina Pavic, Riikka Huhtaniemi, Matti Nykter, Jukka Westermarck
Journal: Cancer Research (2022)

Abstract Protein phosphatase 2A (PP2A) is a tumor suppressor while RAS proteins are potent oncogenes in different cancer types. It is well established that RAS-mediated oncogenic transformation requires simultaneous inhibition of PP2A, but the molecular basis of their interaction is poorly understood. To address the target mechanisms co-regulated by RAS and PP2A we performed a phosphoproteomics screen upon RAS or PP2A manipulation. Overall the results indicated that RAS and PP2A regulate overlapping cellular processes, and that their activities might in particular converge at epigenetic machineries. To study the RAS and PP2A synergy on transcriptional and epigenome regulation we performed multi-omics analysis of cancer cells in which RAS and PP2A activities were modulated. PP2A inhibition resulted in global gene activation while RAS inhibition lead predominantly to gene repression. Use of GFP reporter indicative of epigenetic silencing further confirmed the role of PP2A as a transcriptional repressor and RAS as a transcriptional activator. To investigate the DNA methylation changes and chromatin remodeling effects upon PP2A modulation we used RRBS (Reduced representation bisulfite sequencing) &amp; ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) respectively. PP2A inhibition resulted in global DNA hypomethylation and an open state of chromatin confirming its role as a global repressor of epigenetic processes. To delineate the molecular mechanism behind the transcriptional regulation by RAS and PP2A we monitored the chromatin recruitment of transcriptional repressors upon PP2A or RAS manipulation. Either pharmacological or siRNA mediated PP2A or RAS modulation significantly affected gene repressor complex recruitment to the chromatin. Role of phosphorylation as a critical switch for chromatin repressor complex recruitment was demonstrated by CRISPR/Cas9-mediated mutagenesis of PP2A target phosphorylation site, which also led to a clear phenotype in in vivo tumorigenesis and oncogenic transcription. Collectively these results identify a novel phosphorylation switch on chromatin repressor complex as a converge point of KRAS and PP2A activities in lung cancer. Generally the results provide first indications to global importance of PP2A-mediated phosphorylation regulation in epigenetic gene regulation in cancer. Citation Format: Mukund Sharma, Anna Aakula, Francesco Tabaro, Karolina Pavic, Riikka Huhtaniemi, Matti Nykter, Jukka Westermarck. Chromatin repressor complex as a converge point of RAS and PP2A activities in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2958.
Abstract 2748: High-speed and high-precision FL-based cell count and viability assays using the Cellaca™ MX high-throughput cell counter
Authors: Jordan Bell, Yongyang Huang, Sun Yung, Henry Qazi, Charles Hernandez, Bo Lin, Jean Qiu, Leo Chan
Journal: Cancer Research (2022)

Abstract With multiple FDA-approved cell therapy products available and others in pre-clinical and clinical trials, now, more than ever, it is critical to provide fast and accurate measurements of cell concentration and viability. For certain clinical products, cell concentration is synonymous with dosage, and proper cell viability is crucial to avoidance of potential harmful side effects. The complex nature of patient-derived samples makes legacy cell analysis methods such as the trypan blue exclusion assay difficult or impossible to perform. Nonspecific objects such as RBCs and cellular debris can significantly increase cell counting variation. Meanwhile, the need for cell-based products that are custom-tailored to each patient has resulted in the analysis of smaller and more numerous batches, leading to cell counting bottlenecks. With the challenges of messy samples and counting bottlenecks in mind, we investigate the use of the Cellaca™ MX, a cell counter that can increase throughput and employ fluorescence-based cell counting methods. The high-throughput cell counter can utilize 5 fluorescence imaging channels for cell count and viability analysis in less than 3 min for 24 samples. In addition, fluorescent cell-based assays such as apoptosis (Annexin V or Caspase 3/7), cell cycle, reactive oxygen species measurement can be performed to better characterize the target cell samples. In this work, we demonstrate the capabilities of Cellaca™ MX for high-throughput fluorescence-based cell counting. Comparison among multiple instruments using Jurkat cells and fluorescent beads reveals high consistency between replicate counts, between Cellaca consumable plates, and between instruments. We also compare cell counts made on the Cellaca™ MX with manual counts performed using a hemocytometer, as well as counts performed using other fluorescence-based automated cell counting methods. In addition, we illustrate the use of the ISO 20391-II cell counting standard to evaluate and compare the performance of cell counting methods. Finally, we include real-world primary T cell linearity results over a 4-log range of concentration. The results of the experiments confirm the suitability of the Cellaca™ MX for general fluorescence-based assays applicable to cell therapy-related workflows. Citation Format: Jordan Bell, Yongyang Huang, Sun Yung, Henry Qazi, Charles Hernandez, Bo Lin, Jean Qiu, Leo Chan. High-speed and high-precision FL-based cell count and viability assays using the Cellaca™ MX high-throughput cell counter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2748.
Shared and specialized coding across posterior cortical areas for dynamic navigation decisions
Authors: Shih-Yi Tseng, Selmaan N. Chettih, Charlotte Arlt, Roberto Barroso-Luque, Christopher D. Harvey
Journal: Neuron (2022)

Animals adaptively integrate sensation, planning, and action to navigate toward goal locations in ever-changing environments, but the functional organization of cortex supporting these processes remains unclear. We characterized encoding in approximately 90,000 neurons across the mouse posterior cortex during a virtual navigation task with rule switching. The encoding of task and behavioral variables was highly distributed across cortical areas but differed in magnitude, resulting in three spatial gradients for visual cue, spatial position plus dynamics of choice formation, and locomotion, with peaks respectively in visual, retrosplenial, and parietal cortices. Surprisingly, the conjunctive encoding of these variables in single neurons was similar throughout the posterior cortex, creating high-dimensional representations in all areas instead of revealing computations specialized for each area. We propose that, for guiding navigation decisions, the posterior cortex operates in parallel rather than hierarchically, and collectively generates a state representation of the behavior and environment, with each area specialized in handling distinct information modalities.
Role of allogeneic transplantation in chronic myelomonocytic leukemia: an international collaborative analysis
Authors: Marie Robin, Liesbeth C. de Wreede, Eric Padron, Katerina Bakunina, Pierre Fenaux, Linda Koster, Aziz Nazha, Dietrich W. Beelen, Raajit K. Rampal, Katja Sockel, Rami S. Komrokji, Nico Gagelmann, Dirk-Jan Eikema, Aleksandar Radujkovic, Jürgen Finke, Victoria Potter, Sally B. Killick, Faezeh Legrand, Eric Solary, Angus Broom, Guillermo Garcia-Manero, Vittorio Rizzoli, Patrick Hayden, Mrinal M. Patnaik, Francesco Onida, Ibrahim Yakoub-Agha, Raphael Itzykson
Journal: Blood (2022)
Abstract 5878: The prognostic model of colorectal liver metastases contribute extended molecular profiling
Authors: Chunhui Cui, Xintong Wang
Journal: Cancer Research (2022)

Abstract Background: Over half of colorectal cancer (CRC) patients will metastasize at the same/different times, Only 15-20% of patients are considered resectable at the time of diagnosis. The clinical situation attributed to the clinical heterogeneity of metastatic colorectal cancer(mCRC), the prognosis of patients with mCRC at different metastatic sites is different. The proportion of higher is colorectal liver metastasis (CRLM) and the mechanism of CRLM is complicated,studies have found cancer-related genes expand the predictive molecular profile of survival, The aim of this analysis was to verify and further develop the genetic risk scores. Methods: In this study, bioinformatics methods were used to comprehensively analyze the CRLM cohort (n=270) in the database. The cohort patients were divided into high-risk group and low-risk group. Independent data (n=105) verified the prognostic validity of the model. Results: The models established by commonly genes(APC, BRAF, ERBB2, KRAS, NRAS, PIK3CA, TP53, SMAD2-4) of CRLM were confirmed by prognostic markers. Differences between high-risk prognostic groups compared to low-risk were significant (HR = 1.9023, 95% CI: 1.61-2.23, P_value &amp;lt;0.001), risk score can be used as biomarkers for constructing prognosis. we found significantly higher proportion of low-risk group diagnosed in stage I (82% vs 18%, P_value = 0.035), This model can distinguish in diagnosed stage I CRLM patients with poor prognosis, the model also has a good prognostic effect in validating data and clinical staging. Conclusions: We found that the survival OS of the model risk-high cohort was significant, and is helpful for subsequent treatment.The model risk score was established to be superior to common biomarkers for CRLM, and the discovery of the model is helpful for find metastatic progression the treatment of patients with CRLM. Citation Format: Chunhui Cui, Xintong Wang. The prognostic model of colorectal liver metastases contribute extended molecular profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5878.
Abstract 1723: Spatial analysis of tumor-infiltrated immune cells with highly specific RNAscope™ RNA-protein Co-detection assays
Authors: Anushka Dikshit, Sayantani Basak, Emerald Doolittle, Ilya Kovalenko, Michaeline Bunting
Journal: Cancer Research (2022)

Abstract Interrogating complex tumor microenvironment requires a multi-omics approach that can provide high level of sensitivity and specificity. Identifying immune cell subsets within the tumor can be vital for predicting response and determining therapeutic efficacy. Detecting target immune cell markers using immunohistochemistry/Immunofluorescence (IHC/IF) and visualizing cytokine expression with in situ hybridization (ISH) can provide comprehensive information about the activation states of immune cells. Here, we demonstrate a newly developed integrated ISH and IHC/IF workflow compatible with manual and automated platforms that can substantially improve RNA-protein co-detection. We demonstrate the use of our RNA-Protein Co-detection assay in combination with the automated RNAscope Multiplex Fluorescent v2 assay, automated RNAscope Chromogenic Duplex assay and manual RNAscope Multiplex Fluorescent v2 assay to detect T cell markers, macrophage markers and checkpoint markers in the tumor microenvironment by using a microarray with different tumor samples. We identified CD4+ helper T cells and CD8+ cytotoxic T lymphocytes. Additionally, we determine the activation states of CD8+ T cells by visualizing IFNG, GZMB and IL-2 expression. We were also able to identify macrophages detected by CD68 protein expression and the M1 and M2 subsets were differentiated by using the M2-specific marker, CD163. We could also delineate tumor-stroma border in the samples by using the Pan-CK probe which distinctly marks the tumor cells and visualize the expression of immunoregulatory receptors PD-L1 and CTLA4 in the tumor cells. This assay is enabled for multiplexing by combining with our fluorescent assay platforms. Similarly, for researchers interested in detecting target expression while retaining morphological context, the codetection assay should be combined with our chromogenic assays. Overall, the new RNAscope-ISH-IHC co-detection workflow and reagents enable optimized simultaneous visualization of RNA and protein targets by enhancing the compatibility of antibodies with minimal optimization. Citation Format: Anushka Dikshit, Sayantani Basak, Emerald Doolittle, Ilya Kovalenko, Michaeline Bunting. Spatial analysis of tumor-infiltrated immune cells with highly specific RNAscope™ RNA-protein Co-detection assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1723.
Abstract 5873: Distinct prevalence and spectrum of germline cancer susceptibility gene mutations between early-onset and late-onset colorectal caner
Authors: Zhidong Gao, Jing Zhou, Ying Xin, Bin Liang, Kai Shen, Peng Guo, Kewei Jiang, Mujun Yin, Xiaodong Yang, Zhanlong Shen, Hui Zhang, Depei Huang, Yingjiang Ye
Journal: Cancer Research (2022)

Abstract Background: In the past few decades, the incidence of early-onset CRC (&amp;lt;50 years of age) has increased globally. Previous studies with small sample sizes have shown that early-onset CRC appears to have a distinct clinical, pathologic, and molecular features compared to late-onset CRC (≥ 50 years of age). However, few studies in a large population have focused on the differences in germline gene mutation spectrums of these two groups of patients. Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in 5080 colorectal patients in a CAP/CLIA-approved laboratory (3DMed). NGS testing for germline mutations and MSI was implemented. Results: Of 5080 colorectal patients, early-onset CRC was observed in 1305 (25.7%) patients. The incidence of germline mutation was higher in early-onset CRCs than late-onset CRCs (8.97% vs. 4.15%,OR=2.27, P&amp;lt;0.0001). Consistently, the frequency of MSI-H was higher in early-onset CRCs (13.0% vs. 5.7%, OR=2.48, P&amp;lt;0.0001). The most frequently mutated gene was MLH1 (3.07%) in early-onset CRCs, followed by MSH2 (1.69%), APC (1.0%), MSH6 (0.84%), PMS2 (0.38%), RAD50 (0.31%), CHEK2 (0.31%), MUTYH (0.23%), BRCA1 (0.23%), and BRCA2 (0.23%). The frequency of MMR gene mutations among early- and late-onset patients was 5.98% and 1.27%, respectively (OR=4.95, P&amp;lt;0.0001). MMR gene mutations accounted for 60% of germline mutations of early-onset patients, while this percentage was lower for late-onset CRC (30%). Higher frequencies of APC, RAD50 and CHEK2 gene mutations were associated with early-onset CRCs (all P&amp;lt;0.05). The mutation frequencies of other DDR genes, MUTYH, BRCA1, BRCA2, ATM, ATR, FANCD2, TP53, were not statistically different between the two groups. The late-onset CRC tended to harbor a wider spectrum of germline cancer gene mutations, including an additional 14 cancer-related gene that were not found in early-onset CRC. Conclusions: Our findings revealed different prevalence and spectrum of germline cancer gene mutations between early-onset and late-onset CRC, suggesting that young patients should be specially considered. Citation Format: Zhidong Gao, Jing Zhou, Ying Xin, Bin Liang, Kai Shen, Peng Guo, Kewei Jiang, Mujun Yin, Xiaodong Yang, Zhanlong Shen, Hui Zhang, Depei Huang, Yingjiang Ye. Distinct prevalence and spectrum of germline cancer susceptibility gene mutations between early-onset and late-onset colorectal caner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5873.
Incidence of and Risk Factors for Keratinocyte Carcinoma After Pediatric Solid Organ Transplant
Authors: Muskaan Sachdeva, Irene Lara-Corrales, Elena Pope, An-Wen Chan, Rulan S. Parekh, Abhijat Kitchlu, Cathryn Sibbald
Journal: JAMA Dermatology (2022)

This cohort study identifies the risk factors for and the incidence of keratinocyte carcinoma among patients who underwent solid organ transplant during childhood compared with the general population in Ontario, Canada.